1. Field of the Invention
This invention relates to an improved and economical process for the preparation of 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine, which is also known as lamotrigine. This is a new structural class of antiepileptic drug.
2. Description of the Prior Art
The need for a drug, which will be effective in the patients who do not satisfactorily respond to conventional antiepileptic drugs has always been there. Also, a selectivity of specific mechanism of action reduces the side effect burden as in the case with Lamotrigine i.e. 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine (I). Lamotrigine, the selective sodium channel blocker which inhibits synaptosomal excitatory neurotransmitter release, is a use and voltage dependent inhibitor of presynaptic sodium channels. ##STR1##
Lamotrigine can be prepared according to the literature procedure described in the U.S. Pat. No. 4,602,017 which comprises reacting 2,3-dichloro acyl chloride with cuprous cyanide and potassium iodide in dry xylene medium and reacting the resultant dichloro acyl cyanide with aminoguanidine bicarbonate and cyclizing the reaction product in presence of 10% methanolic KOH or n-propanol to produce lamotrigine.
In the U.S. Pat. No. 4,602,017, acid chloride (II) (1 mole equivalent) was converted to acyl cyanide (III) (Reaction-1) by using metal cyanide viz. copper cyanide (.about.2.4 mole equivalent) and potassium iodide (.about.2.4 mole equivalent) in dry xylene (.about.20 vol./wt of acid chloride) as solvent. ##STR2##
In the reaction of acid chloride (II) to acyl cyanide (III) as in the Reaction-1, the voluminous quantities of solvent dry xylene, demands the larger reactor size for comparatively smaller quantities of acid chloride.
Also, the use of potassium iodide increases the cost of the process. In the final step of cyclization, an alcoholic solvent i.e. alcoholic KOH further adds up to the cost.
The activation of copper cyanide by using metal iodide is certainly noteworthy.
However, taking into view the cost of metal iodide viz. potassium iodide, the subject invention looks into the possibility of avoiding the use of it, to reduce the manufacturing cost. Moreover, use of the solvent viz.dry xylene, in such a large quantities adds to the cost of the product.